The overall goals of this work are to define the neural mechanisms through which gastrointestinal peptides, especially cholecystokinin (CCK), reduce food intake and ultimately to appreciate how these substrates are involved in the physiology and pathology of food intake and body weight. CCK is released by intestinal mucosal I cells, in response to nutrients in the intestine. CCK also is synthesized and secreted by discrete populations of neurons in the brain. Recent evidence suggests that in addition to controlling the size of individual meals, CCK may also contribute to the control of long-term food intake and body weight gain. The mechanisms by which CCK contributes to control of long-term food intake and body weight gain have not be investigated. However, recent findings suggest that control of long-term food intake and body weight is facilitated by synergistic interactions between CCK and the fat cell hormone, leptin. In addition, preliminary results from our laboratory indicate that CCK receptors in the hypothalamus play an integral role in the control of long-term food intake and body weight by CCK. The experiments proposed in the attached application will investigate the participation of CCK and CCK receptors in the control of long-term food intake and body weight by testing three hypotheses. First we will use surgical and intestinal infusion methodology to test the hypothesis that exogenous CCK and endogenous CCK both enhance the effect of brain leptin on weight loss and reduction of food intake by actions on capsaicin-sensitive afferent neurons and CCK-A receptors. Second, using intestinal, arterial and intravenous peptide infusions we will test the hypothesis that leptin acts directly on vagal afferent neurons alone and/or in concert with CCK to reduce short-term food intake and enhance leptin effects on long-term food intake. Finally, we will us a novel targeted toxin to selectively destroy specific populations of brain neurons that express CCK receptors, in order to test the hypothesis that discrete populations of CCK receptive hypothalamic neurons participate in control of long-term daily food intake and body weight gain. These experiments are intended to explore an expanded role for control of body weight by both central and peripheral CCK receptors. Such a role could well be of seminal importance to understanding the mechanism by which body weight and food intake are controlled in health and disease.